As more than 7,000 cell and gene therapies progress through the development pipeline and only 152 CMOs have the capabilities to manufacture them, production bottlenecks are the major obstacle to large-scale commercial manufacture once more Advanced Therapy Medicinal Products (ATMPs) are approved, experts say.
In a panel discussion called “Discover/Develop: But How Will you Manufacture Your Therapeutic?” at BIO Digital Conference 2020 on June 8, John Erickson, Chief Technology Officer at NIIMBL (Newark, DE, US), said the problems lie with “flexibility, process control, speed, sustainability, and capital costs.” Bottlenecks, especially in viral vector manufacturing, and slow processing will limit wide-scale commercial manufacture of ATMPs, he said.
Panellist Sue Behrens, Professor in Bioprocessing and Director of the Amgen Bioprocessing Center at Keck Graduate Institute (Claremont, CA, US), agreed, highlighting product stability and sterility as the big challenges, stemming from a poor understanding of how technologies interact. Process control for ATMPs is inherently difficult due to variability in the biologic starting material, but real-time biosensor readings could fix this by allowing adjustments during the process, she said.
The largest CMOs are predicting great future demand and have significantly invested in ATMP manufacturing capabilities. In May 2019, Thermo Fisher Scientific (Waltham, MA, US) acquired Brammer Bio (Cambridge, MA, US) for $1.7B, and Catalent (Somerset, NJ, US) acquired Paragon Bioservices (Baltimore, MD, US) for $1.2B in May 2019 and later MaSTherCell Global (Hainaut, Belgium) for $315M in February 2020. Despite demand being unpredictable and many problems still existing with the ATMP manufacturing process, there has been consistent and sustained spending on enhancing related capabilities (particularly for the viral vector bottleneck issue) even over recent months, as Table 1 shows.
Table 1: CMO Investments in API Biologics – Cell, Gene, Vaccine, and Virus, April–July 2020
Currently, there are only 34 marketed gene and cell therapies globally. It is a relatively new and high-value treatment, with Gilead Sciences Inc’s (Foster City, CA, US) Yescarta (axicabtagene ciloleucel), Novartis AG’s (Basel, Switzerland) Zolgensma (onasemnogene abeparvovec-xioi), and Novartis’ Kymriah (tisagenlecleucel) being particularly lucrative in terms of 2019 revenues. However, as Figure 1 shows, there are a large number of ATMPs in the drug pipeline. In future, they will become increasingly approved and therefore improvements to the production process are required to remove manufacturing bottlenecks and enable cost-efficient manufacture at a commercial scale.
Figure 1: Advanced Therapy Medicinal Products in the Drug Pipeline
Source: GlobalData, Pharma Intelligence Center Drugs Database (Accessed: 8 July 2020) © 2020 GlobalData Plc.
Notes: Pipeline drugs are in Discovery, Preclinical, IND/CTA Filed, Phase 0, Phase I, Phase II, Phase III, and Pre-Registration stages
Producing gene or cell therapies requires an inherently high level of manufacturing expertise and expensive facility requirements many pharma companies do not possess. Figure 2 assesses the current manufacturing source outlook and CMO opportunities for 12 cell or gene therapies approved in the US or EU and whose manufacturing arrangements are publicly disclosed. Many of the sponsors for these products are large-cap ($10B–100B) or mega-cap (>$100B) companies, which typically choose to invest in developing their own manufacturing facilities. However, API, dose, and packaging have been outsourced for 39%, 26%, and 29% of ATMPs respectively, proving that significant opportunities exist for CMOs. Licensor/Partner agreements accounted for 5–6% of all manufacturing relationships.
Based on these findings, there are considerable opportunities for CMOs with the capabilities to manufacture ATMPs. However, only 152 CMOs have the capability to produce cell or gene therapy API for global markets and of these only 121 are dedicated contract CMOs, according to the Contract Service Provider database.
Figure 2: Manufacturing Sources for Gene and Cell Therapies Approved in US/EU
Source: GlobalData, Pharma Intelligence Center Drugs by Manufacturer Database (Accessed: 8 July 2020) © 2020 GlobalData Plc